The tachykinins are an evolutionarily conserved family of amidated peptides. The family name tachykinin refers to the ability to induce fast, immediate contractile responses of smooth muscle preparations (as opposed to bradykinin, which elicits a slow contraction). The first family member to be isolated and characterized was substance P (Von Euler and Gaddum, J. Physiology London 72:74-86 (1931)), which caused peripheral vasodilation and stimulated intestinal muscle contractions. Other members of the tachykinin family include substance K (or neurokinin A; Nawa et al., Life Sci. 34:1153-1160 (1984)) and neuromedin K (or neurokinin B; Kangawa et al., Biophys. Res. Commun. 114:533-540 (1983)). Neuropeptide K and neuropeptide γ, which are N-terminally extended forms of neurokinin A, are also included in the family (Tatemoto et al., Biophys. Res. Commun. 128:947-953 (1985); Kage et al. J. Neurochem. 50:1412-1417 (1988)). All tachykinin peptides share the C-terminal pentapeptide—FXGLMa.
Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) are derived from two precursor-encoding genes (Nawa et al., Nature 312:729-734 (1984); Kotani et al., Proc. Natl. Acad. Sci. USA 83:7074-7078 (1986)). Preprotachykinin A (PPTA) codes for SP and NKA, while preprotachykinin B (PPTB) codes for NKB. As a consequence of alternative splicing, three distinct mRNAs are produced from the primary PPTA transcript (α-PPTA, β-PPTA, and γ-PPTA), all of which code for SP (Nawa et al., Nature 312:729-734 (1984)). Interestingly, α-PPTA does not include the sixth exon that codes for NKA, β-PPTA contains all exons, and γ-PPTA does not contain the fourth exon. As a result, cells that exclusively express α-PPTA mRNA only produce SP. When β-PPTA is expressed, SP, NKA, or neuropeptide K can be synthesized. γ-PPTA gives rise to SP, NKA, or neuropeptide γ. This alternative RNA and polypeptide precursor processing appears to be an important mechanism in creating structural diversity and tissue-specific differences in the expression of tachykinin neuropeptides. PPTB is cleaved at both the N- and C-terminus to yield the mature form of neurokinin B (amino acids 81 to 90 of SEQ ID NO:2).
The tachykinins exhibit a wide variety of functions. A hallmark feature is their ability to induce contractile responses in smooth muscle. Additional biologic roles include vasodilatation in hypotension, mucous and pancreatic secretion, pain transmission, neurogenic inflammation, and regulation of the immune system (Longmore et al., Canadian J. Physiol. Pharmacol. 75:612-621 (1997)). Tachykinins are normally restricted to the central nervous system and exert their effects peripherally by their release from nerve endings. Three membrane receptors that recognize the tachykinins have been identified as NK1R, NK2R, and NK3R. Their preferential endogenous ligands are substance P, neurokinin A, and neurokinin B, respectively. Differences at the amino terminal end of the tachykinins determine their receptor affinities. All three receptors interact with G proteins and have a structure consisting of seven hydrophobic transmembrane regions. Although many protease enzymes are active in degrading tachykinins, the in vivo stability is mainly regulated by angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP; Skidgel et al. Peptides 5:769-776 (1984)).
Tachykinins have a large number of in vivo functions, as well as regulated expression patterns. Accordingly, promoting and inhibiting such peptides has wide therapeutic application. There is a clear need, therefore, for identification and characterization of compositions, such as antibodies, that influence the biological activity of tachykinins, both normally and in disease states. In particular, there is a need to isolate and characterize antibodies that modulate the biological activities of neurokinin B for the treatment of pre-eclampsia, hypertension, inflammation, asthma, gastrointestinal disorders, anxiety, depression, addiction, or pain.